Within the last few years, my laboratory and others have generated considerable data supporting the hypothesis that a moderate fever is a host defense response to bacterial infection (see Kluger 1979e for review). In addition, there is some evidence that during infection a synergism exists between the observed changes in trace metals (e.g. plasma iron and zinc fall and copper rises) and the development of a fever in terms of enhancing the host defenses against infectious organisms. For example, we have recently shown that the changes in plasma concentration of iron, coupled with an elevation in temperature, does lead to a decrease in the in vitro growth rate of certain pathogenic bacteria (Grieger & Kluger, 1978; Kluger & Rothenburg, 1979a). In addition plasma obtained from noninfected rabbits supports the growth of P. multocida at temperatures corresponding to afebrile and febrile rabbits; but, plasma obtained from infected rabbits only supports the growth of these pathogens at afebrile temperatures (Kluger & Rothenburg, 1979b). It is possible that the changes which occur in the plasma concentrations of trace metals are responsible (for all or part) of the decreased growth rate of the bacteria at febrile temperatures. We now plan to investigate in more detail the possible synergistic host defense role of fever and the changes in trace metals. One group of experiments will involve the effect of (a) endogenous pyrogen (a protein which both alters plasma trace metals and induces a fever), (b) zinc chloride, (c) copper chloride, or (d) lactoferrin (an endogenously produced iron chelator) on the survival rate of bacterially infected rabbits. The other type of experiment will be a continuation of our studies on the growth rate of bacteria in plasma obtained from infected and noninfected rabbits in order to determine the factors responsible for the inhibition of microbial growth in the plasma from infected rabbits at the febrile temperature. The results of these investigations could significantly increase our fundamental understanding of host defense responses to infection and have potentially important therapeutic application.